Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

Abstract

Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.

Keywords: Genetic variation; Human Leukocyte Antigen; Innate immunity; Killer-cell immunoglobulin-like receptor; Malaria; Natural killer cells.

Fig. 1

KIR haplotypes. KIR haplotypes A and B are present in all populations worldwide. A recombination hotspot between KIR3DP1 and KIR2DL4 separates the centromeric region from the telomeric end of both types of haplotypes. The KIR A haplotype is mainly composed of inhibitory KIRs, except for KIR2DS4. Allelic polymorphism is very high in the KIR A haplotype (KIR3DL1, 3DL2, and 3DL3 exhibit >100 alleles, and 2DL1 and 2DL3 exhibit ~50 alleles). Haplotype B has several activating receptors, with variable numbers of genes (from 4 to 20 genes) and fewer allelic polymorphisms. Some KIR B haplotypes are composed of combinations of haplotypes A and B (CenA-TelB, CenB-TelA). The HLA epitopes bound by some KIRs are known and are indicated as C1, C2, or Bw4

Fig. 2

NK receptors and responses to malaria. NK cell responses to malaria may be either beneficial, if they target the parasite, or detrimental, if they contribute to immunopathology. The binding of HLA receptors (CD94/NKG2A or KIR) to self HLA molecules affects both how NK cells are primed for function in a steady state and how they function during an immune response. In the steady state, the binding of HLA molecules on hematopoietic cells by inhibitory NK cell receptors such as NKG2A (which binds HLA-E) and KIR (which binds HLA-A, -B, and -C) primes NK cells to make them functionally competent. The process of acquiring functional competence through the binding of inhibitory receptors to self HLA molecules on hematopoietic cells is referred to as NK cell education. The binding of the same inhibitory receptors to HLA molecules on potential target cells during an immune response, however, suppresses NK cell function. a For example, CD56^bright NK cells that do not express KIR can be educated by NKG2A binding to HLA-E to produce IFN-γ during the immune response to malaria. On the other hand, CD56^dim NK cells that express inhibitory KIRs (e.g., KIR2DL1 or KIR3DL1 in a KIR A haplotype) for self HLA (e.g., HLA-C2 or HLA-Bw4, respectively) found on hematopoietic cells are educated to recognize and kill infected red blood cells that do not express HLA molecules and therefore cannot suppress KIR2DL1+ and KIR3DL1+ CD56^dim NK cells during immune responses to blood-stage malaria. CD56^dim cells can also mediate ADCC because they express CD16, which binds antibodies through its Fc domain. b Liver NK cells are composed of different subsets, some of which express both KIR and NKG2A, and both of these receptors can educate liver NK cells by binding HLA-A, -B, -C, or -E on hematopoietic cells in a steady state. On the other hand, during liver-stage malaria, both receptors can suppress NK cell functions when NK cells interact with infected hepatocytes that express cognate HLA molecules